title: Extension of the germinal center stage of B cell development promotes autoantibodies in BXD2 mice.
abstract: OBJECTIVE
  Regulator of G protein signaling (RGS) proteins inhibit chemokine signaling by desensitizing G protein-coupled receptor signals. This study was undertaken to determine the mechanisms by which RGS13 promotes the generation of pathogenic autoantibodies in germinal centers (GCs), using BXD2-Rgs13-/- mice.
  
  
  METHODS
  Confocal and light microscopy imaging techniques were used to determine the location of cells that express RGS13 and activation-induced cytidine deaminase (AID) in the mouse spleen, and the number of plasmablasts. The levels of GC and plasma cell program transcripts in GC B cells were determined by real-time quantitative polymerase chain reaction (qPCR). Differential interleukin-17 (IL-17)-mediated expression of RGS13 in GC versus non-GC B cells was analyzed using A20 and 70Z/3 B cells.
  
  
  RESULTS
  In the spleens of BXD2 mice, RGS13 was mainly expressed by GC B cells and was stimulated by IL-17 but not IL-21. IL-17 up-regulated RGS13 in A20 GC cells but not 70Z/3 non-GC B cells. BXD2- Rgs13-/- mice exhibited smaller GCs and lower AID levels, suggesting lower somatic hypermutation and affinity maturation. However, GC B cells from BXD2- Rgs13-/- mice showed increased levels of IgMbright plasmablasts, up-regulation of the genes encoding plasma program, including interferon regulatory factor 4, B lymphocyte-induced maturation protein 1, and X-box binding protein 1 and the p-CREB target genes Fosb and Obf1, and down-regulation of the GC program genes Aid, Pax5, and Bach2 compared to BXD2 mice. BXD2-Rgs13-/- mice had lower titers of IgG autoantibodies and IgG deposits in the glomeruli, suggesting reduced autoantibody pathogenicity.
  
  
  CONCLUSIONS
  RGS13 deficiency is associated with a reduction in GC program genes and the exit of fewer pathogenic IgM plasmablasts in BXD2 mice. Our findings indicate that prolonged GC program, mediated by up-regulation of RGS13, enhances AID expression and enables the generation of pathogenic autoantibodies in autoreactive GCs.
authors.affiliation: University of Alabama at, Birmingham.
authors.forename: John H
authors.initials: JH
authors.lastname: Wang
authors.forename: James S
authors.initials: JS
authors.lastname: New
authors.forename: Shutao
authors.initials: S
authors.lastname: Xie
authors.forename: PingAr
authors.initials: P
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Bao
authors.initials: B
authors.lastname: Luo
authors.forename: Yanna
authors.initials: Y
authors.lastname: Ding
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hsu
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018858:Germinal Center / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020381:Interleukin-17 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020710:RGS Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000098546:Interleukin-21
chemical_list: D001323:Autoantibodies; D020381:Interleukin-17; D007378:Interleukins; D020710:RGS Proteins; C586224:RGS13 protein, mouse; D000098546:Interleukin-21